Celiac disease (CD, gluten-sensitive enteropathy, celiac sprue) is a common disease with significant morbidity if untreated. It is caused by sensitivity to the dietary protein gluten, which is present in wheat, rye and barley. The term gluten-sensitive enteropathy refers to the histologic abnormality of the small intestine. It is now recognized to be a common disease, with reports that the disease frequency is 1:150 in the US, similar to European estimates. Before the development of highly specific and sensitive antibody tests, CD was under-diagnosed. Recently, it has been proposed that in addition to better diagnosis, CD is also increasing in incidence. Occult disease is frequently present with minimal classic symptoms or signs. The ratio of symptomatic to asymptomatic CD is estimated to be 1:7. Some complications of CD include lymphoma, osteoporosis, anemia, miscarriages, seizures, vitamin deficiencies, and co-occurrence of other autoimmune diseases. No pharmacological treatment is available. Although treatment with a gluten-free diet will improve symptoms, recurrence of symptoms and complications may occur after minor dietary indiscretions. There are several unaddressed public health concerns that will be focused on in this proposal. Do individuals at high risk of CD warrant continued screening and are there putative stress events that trigger the disease in susceptible individuals? Does the early detection of CD by screening reduce the risk of development of additional autoimmune disorders that are known to be associated with CD? Are individuals diagnosed with CD at higher risk of developing other autoimmune diseases and additional symptoms if they do not adhere to a gluten-free diet? To investigate these questions, we will recontact individuals previously enrolled in two family studies, one at the University of California Irvine and one at Mayo Clinic, in which we had systematically performed serologic and HLA testing and collected symptom data for family members from CD families. Aim 1 is to investigate the development of CD in first-degree relatives of CD cases who previously tested negative five or more years ago. We will perform serologic testing for CD and have the subjects complete a follow-up questionnaire including data items on general health, CD symptoms, associated-diseases, diet, and major life events as potential triggers for CD. Aim 2 is to investigate the prevalence of auto-antibodies that serve as biomarkers for thyroiditis, type I diabetes, pernicious anemia, and rheumatoid arthritis in CD cases. We will obtain new sera and follow-up questionnaires from CD cases diagnosed at least five years ago. This study will address two critical public health management issues in CD: 1) whether retesting is necessary for those at high-risk who have previously tested negative;and 2) whether the association of CD with other auto-immune diseases can be mitigated by following a gluten-free diet. These results will provide information to facilitate translation into clinical management of the disease and its comorbid conditions.This proposal is focused on the public health implications of celiac disease, a common disease with a population prevalence of 1:150 in the US. First, we will determine whether a single test for celiac disease in individuals at high risk of disease is adequate or whether repeat testing is necessary. Second, we will determine the impact of celiac disease on the development of other autoimmune diseases, and whether adherence to a gluten-free diet can prevent development, delay onset, or reduce symptoms of other auto-immune diseases.